Sigma receptors are orphan receptors. There are two subtypes of sigma receptors, sigma-1 and sigma-2. Although sigma-1 receptors promote cell growth and thus inhibit cell death, activation of sigma-2 receptors triggers cell death. Sigma receptors has high levels in the central nervous system (CNS) and in cancer. They exhibit a high affinity for compounds with psychotropic activity. Sigma receptors have significant potential for the development of antipsychotic drugs. It also has the potential for the treatment of drug addiction and other CNS diseases. In this study, Siramesine is a sigma-2 receptor agonist. Siramesine has a subnanomolar affinity for sigma-2 receptors (Kd=0.12 nM) and exhibits a 140-fold selectivity for sigma-2 receptors over sigma-1 receptors (Kd=17 nM).
Siramesine is a potent inducer of cell death. In HaCaT cells, cell death is accompanied by caspase activation, rapid loss of mitochondrial membrane potential (MMP), cytochrome c release, cardiolipin peroxidation and typical apoptotic morphology. However, in U-87MG cells most apoptotic hallmarks are not notable, although MMP is rapidly lost. Furthermore, Siramesine induces rapid cell death at concentrations above 20 μM, which was accompanied by the loss of mitochondria integrity and caspase activation and reactive oxygen species (ROS) generation. It also induces lysosomal leakage and cathepsin-dependent death of cancer cells in vitro and displays potent anti-cancer activity in vivo. Siramesine rapidly induces the loss of MMP and ROS generation. It also induces major ultrastructural changes in cells. In addition, Siramesine prevents autophagosome fusion with lysosomes.
In summary, Siramesine induces cell death at low micromolar concentrations in a number of cell lines of different origin. The mitochondria, and not lysosomes, are critical organelles for the induction of cell death.